Changes in amniotic fluid concentration of thrombin–antithrombin III complexes in patients with preterm labor: Evidence of an increased thrombin generation

Abstract

Objective Preterm labor is associated with excessive maternal thrombin generation as evidenced by increased circulating thrombin–antithrombin (TAT) III complexes concentration. In addition to its hemostatic functions, thrombin has uterotonic properties that may participate in the mechanism leading to preterm birth in cases of intrauterine bleeding. Thrombin also has a proinflammatory role, and inflammation is associated with increased thrombin generation. The aim of this study was to determine whether intra-amniotic infection/inflammation (IAI) is associated with increased amniotic fluid (AF) thrombin generation in women with preterm and term deliveries. Study design This cross-sectional study included the following groups: 1) mid-trimester (n=74); 2) term not in labor (n=39); 3) term in labor (n=25); 4) term in labor with IAI (n=22); 5) spontaneous preterm labor (PTL) who delivered at term (n=62); 6) PTL without IAI who delivered preterm (n=59); 7) PTL with IAI (n=71). The AF TAT III complexes concentration was measured by ELISA. Non-parametric statistics were used for analysis. Results 1) TAT III complexes were identified in all AF samples; 2) patients with PTL who delivered preterm, with and without IAI, had a significantly higher median AF TAT III complexes concentration than those with an episode of PTL who delivered at term (p<0.001, p=0.03, respectively); 3) among patients with preterm labor without IAI, elevated AF TAT III complexes concentration were independently associated with a shorter amniocentesis-to-delivery interval (hazard ratio- 1.5, 95%CI, 1.07–2.1); 4) among patients at term, those with IAI had a higher median AF TAT III complexes concentration than those without IAI, whether in labor or not in labor (p=0.02); 5) there was no significant difference between the median AF TAT III complexes concentration of patients at term with and without labor; and 6) patients who had a mid-trimester amniocentesis had a lower median AF TAT III complexes concentration than that of patients at term not in labor (p<0.001). Conclusions We present herein a distinct difference in the pattern of intra-amniotic thrombin generation between term and preterm parturition. Preterm labor leading to preterm delivery is associated with an increased intra-amniotic thrombin generation, regardless of the presence of IAI. In contrast, term delivery is associated with an increased intra-amniotic thrombin generation only in patients with IAI.

Placental bed disorders in preterm labor, preterm PROM, spontaneous abortion and abruptio placentae

“…66 When uteroplacental ischemia is severe enough to lead to decidual necrosis and hemorrhage, thrombin may activate the common pathway of parturition. Evidence in support of this includes: 1) decidua is a rich source of tissue factor, the primary initiator of coagulation; 67 2) intrauterine administration of whole blood to pregnant rats stimulates myometrial contractility, 68 while heparinized blood does not (heparin blocks the generation of thrombin); 68 3) fresh whole blood stimulates myometrial contractility in vitro , and this effect is partially blunted by incubation with hirudin, a thrombin inhibitor; 68 4) thrombin stimulates myometrial contractility in a dose-dependent manner; 68 5) thrombin stimulates the production of MMP-1 69 , urokinase type plasminogen activator (uPA), and tissue type plasminogen activator (tPA) by endometrial stromal cells in culture; 70 matrix metalloproteinase-1 can digest collagen directly, while uPA and tPA catalyse the transformation of plasminogen into plasmin which, in turn, can degrade type III collagen and fibronectin, 71 important components of the extracellular matrix in the chorioamniotic membranes; 72 6) thrombin/anti-thrombin (TAT) complexes, markers of in vivo generation of thrombin, are increased in the plasma 73 and amniotic fluid 74 of women in preterm labor and with preterm PROM; 7) an elevation of plasma TAT complex concentration in the second trimester is associated with subsequent preterm PROM; 75 8) the presence of retroplacental hematoma detected by ultrasound examination in the first trimester is associated with adverse pregnancy outcomes, including preterm birth and fetal growth restriction; 76 and 9) the presence of vaginal bleeding in the first or second trimester is associated with preterm birth and other adverse perinatal outcomes. 77–80 …”

Clinical chorioamnionitis is characterized by changes in the expression of the alarmin HMGB1 and one of its receptors, sRAGE

“…We have examined the changes of amniotic fluid concentrations of pro-inflammatory cytokines [46–54], anti-inflammatory cytokines [55], chemokines [56–62], proteases/anti-proteases [63], matrix-metalloproteinase [64–71], pro- and anti-angiogenic factors [72–74], coagulation factors [75,76], adipocytokines [77–79], anti-microbial peptides [80] and prostaglandins [81–84] in patients with intra-amniotic infection /inflammation (IAI) both at term and preterm gestations. Amniotic fluid concentrations of sRAGE and esRAGE have been reported to be elevated in patients with IAI in preterm gestations and decreased in labor at term [85], whereas the amniotic fluid concentration of HMGB1 in patients at term with clinical chorioamnionitis has not yet been examined.…”

Infection-induced thrombin production: a potential novel mechanism for preterm premature rupture of membranes (PPROM)

“…Thrombin generation has been associated with fetal membrane weakening and PPROM 50, 54 , and treatment of amnion explants with thrombin results in increased levels of matrix metallopeptidase 9 (MMP9) and mechanical weakening 55 . However, thrombin generation in fetal membranes and the source of thrombin in amniotic fluid is not well described 47, 56 . Decidual hemorrhage associated with either intrauterine infection 57 or bleeding in pregnancy 58 is thought to be a primary source of thrombin.…”